Degenerative Aortic Stenosis, Dyslipidemia and Possibilities of Medical Treatment.

Degenerative aortic stenosis (DAS) is the most frequently diagnosed heart valve disease in Europe and North America. DAS is a chronic progressive disease which resembles development of atherosclerosis. Endothelial dysfunction, lipid infiltration, calcification and ossification are evidenced in both diseases. The same risk factors such as older age, male sex, smoking, and elevated levels of lipids are identified. The effect of smoking, visceral obesity, metabolic syndrome, hypercholesterolemia, low-density lipoprotein, high-density lipoprotein, lipoprotein(a), adiponectin and apolipoprotein(a) on development of DAS are being studied. The search for genetic ties between disorders of lipid metabolism and DAS has been started. DAS is characterized by a long symptom-free period which can last for several decades. Aortic valve replacement surgery is necessary when the symptoms occur. The lipid-lowering therapy effect on stopping or at least slowing down the progression of DAS was studied. However, the results of the conducted clinical trials are controversial. In addition, calcium homeostasis, bone metabolism and calcinosis-reducing medication are being studied. Although prospective randomized clinical trials have not demonstrated any positive effect of statins used for slowing progression of the disease, statins are still recommended for patients with dyslipidemia. Recent study has suggested that a specific modification of treatment, based on severity of disease, may have a beneficial effect in patients with aortic sclerosis and mild DAS. New clinical studies analyzing new treatment possibilities which could correct the natural course of the disease and reduce the need for aortic valve replacement by surgery or transcatheter treatment interventions are needed.

Clinical Correlates and Prognostic Value of Plasma Galectin-3 Levels in Degenerative Aortic Stenosis: A Single-Center Prospective Study of Patients Referred for Invasive Treatment.

Galectin-3 (Gal-3), a ß-galactoside-binding lectin, has been implicated in myocardial fibrosis, development of left ventricular (LV) dysfunction and transition from compensated LV hypertrophy to overt heart failure (HF), being a novel prognostic marker in HF. Risk stratification is crucial for the choice of the optimal therapy in degenerative aortic stenosis (AS), affecting elderly subjects with coexistent diseases. Our aim was to assess correlates and prognostic value of circulating Gal-3 in real-world patients with degenerative AS referred for invasive treatment. Gal-3 levels were measured at admission in 80 consecutive patients with symptomatic degenerative AS (mean age: 79 ± 8 years; aortic valve area (AVA) index: 0.4 ± 0.1 cm²/m²). The therapeutic strategy was chosen following a dedicated multidisciplinary team-oriented approach, including surgical valve replacement (n = 11), transcatheter valve implantation (n = 19), balloon aortic valvuloplasty (BAV) (n = 25) and optimal medical therapy (n = 25). Besides routine echocardiographic indices, valvulo-arterial impedance (Zva), an index of global LV afterload, was computed. There were 22 deaths over a median follow-up of 523 days. Baseline Gal-3 correlated negatively with estimated glomerular filtration rate (eGFR) (r = -0.61, p < 0.001) and was unrelated to age, symptomatic status, AVA index, LV ejection fraction, LV mass index or Zva. For the study group as a whole, Gal-3 tended to predict mortality (Gal-3 >17.8 vs. Gal-3 <17.8 ng/mL; hazard ratio (HR): 2.03 (95% confidence interval, 0.88-4.69), p = 0.09), which was abolished upon adjustment for eGFR (HR: 1.70 (0.61-4.73), p = 0.3). However, in post-BAV patients multivariate-adjusted pre-procedural Gal-3 was associated with worse survival (HR: 7.41 (1.52-36.1), p = 0.01) regardless of eGFR. In conclusion, the inverse eGFR-Gal-3 relationship underlies a weak association between Gal-3 and adverse outcome in patients with degenerative AS referred for invasive therapy irrespective of type of treatment employed. In contrast, pre-procedural Gal-3 appears an independent mortality predictor in high-risk AS patients undergoing BAV.

Predictors of coronary and carotid atherosclerosis in patients with severe degenerative aortic stenosis.

BACKGROUND: Patients with degenerative aortic stenosis (AS) exhibit elevated prevalence of coronary artery disease (CAD) and internal carotid artery stenosis (ICAS). Our aim was to investigate prevalence of significant CAD and ICAS in relation to demographic and cardiovascular risk profile among patients with severe degenerative AS. METHODS: We studied 145 consecutive patients (77 men and 68 women) aged 49-91 years (median, 76) with severe degenerative AS who underwent coronary angiography and carotid ultrasonography in our tertiary care center. The patients were divided into two groups according to the presence of either significant CAD (n=86) or ICAS (n=22). RESULTS: The prevalence of significant CAD or ICAS was higher with increasing number of traditional risk factors (hypertension, hypercholesterolemia, diabetes, smoking habit) and decreasing renal function. We found interactions between age and gender in terms of CAD (p=0.01) and ICAS (p=0.06), which was confirmed by multivariate approach. With the reference to men with a below-median age, the prevalence of CAD or ICAS increased in men aged >76 years (89% vs. 55% and 28% vs. 14%, respectively), whereas the respective percentages were lower in older vs. younger women (48% vs. 54% and 7% vs. 17%). CONCLUSIONS: In severe degenerative AS gender modulates the association of age with coronary and carotid atherosclerosis with its lower prevalence in women aged >76 years compared to their younger counterparts. This may result from a hypothetical "survival bias", i.e., an excessive risk of death in very elderly women with severe AS and coexisting relevant coronary or carotid atherosclerosis.

Aortic stenosis: a review on acquired pathogenesis and ominous combination with diabetes mellitus.

BACKGROUND: Aortic stenosis (AS) is a progressive disease, with no pharmacological treatment. The prevalence of diabetes mellitus (DM) among AS patients is higher than in the general population. DM significantly increases the risk of AS development and progression from mild to severe. The interplay between AS and DM's mechanism is not entirely known yet. MAIN BODY: The increased accumulation of advanced glycation end products (AGEs) was linked to increased valvular oxidative stress, inflammation, expression of coagulation factors, and signs of calcification, according to an analysis of aortic stenotic valves. It is interesting to note that in diabetic AS patients, valvular inflammation did not correlate with serum glucose levels but rather only with long-term glycemic management markers like glycated haemoglobin and fructosamine. Transcatheter aortic valve replacement, which has been shown to be safer than surgical aortic valve replacement, is advantageous for AS patients who also have concurrent diabetes. Additionally, novel anti-diabetic medications have been proposed to lower the risk of AS development in DM patients, including sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonist that target reduction of AGEs-mediated oxidative stress. CONCLUSIONS: There are little data on the effects of hyperglycemia on valvular calcification, but understanding the interactions between them is essential to develop a successful treatment strategy to stop or at least slow the progression of AS in DM patients. There is a link among AS and DM and that DM negatively impacts the quality of life and longevity of AS patients. The sole successful treatment, despite ongoing efforts to find new therapeutic modalities, involves aortic valve replacement. More research is required to find methods that can slow the advancement of these conditions, enhancing the prognosis and course of people with AS and DM.

Association of Increased Vascular Stiffness with Cardiovascular Death and Heart Failure Episodes Following Intervention on Symptomatic Degenerative Aortic Stenosis.

BACKGROUND: The resistive (RI) and pulsatile (PI) indices are markers of vascular stiffness (VS) which are associated with outcomes in patients with cardiovascular disease. We aimed to assess whether VS might predict incidence of cardiovascular death (CVD) and heart failure (HF) episodes following intervention on degenerative aortic valve stenosis (DAS). METHODS: The distribution of increased VS (RI ≥ 0.7 and PI ≥ 1.3) from supra-aortic arteries was assessed in patients with symptomatic DAS who underwent aortic valve replacement (AVR, n = 127) or transcatheter aortic valve implantation (TAVI, n = 119). During a 3-year follow-up period (FU), incidences of composite endpoint (CVD and HF) were recorded. RESULTS: Increased VS was found in 100% of TAVI patients with adverse event vs. 88.9% event-free TAVI patients (p = 0.116), and in 93.3% of AVR patients with event vs. 70.5% event-free (p = 0.061). Kaplan-Mayer free-survival curves at 1-year and 3-year FU were 90.5% vs. 97.1 % and 78% vs. 97.1% for patients with increased vs. lower VS. (p = 0.014). In univariate Cox analysis, elevated VS (HR 7.97, p = 0.04) and age (HR 1.05, p = 0.024) were associated with risk of adverse outcomes; however, both failed in Cox multivariable analysis. CONCLUSIONS: Vascular stiffness is associated with outcome after DAS intervention. However, it cannot be used as an independent outcome predictor.

Importance of Increased Arterial Resistance in Risk Prediction in Patients with Cardiovascular Risk Factors and Degenerative Aortic Stenosis.

BACKGROUND: Cardiovascular disease is a leading cause of heart failure (HF) and major adverse cardiac and cerebral events (MACCE). OBJECTIVE: To evaluate impact of vascular resistance on HF and MACCE incidence in subjects with cardiovascular risk factors (CRF) and degenerative aortic valve stenosis (DAS). METHODS: From January 2016 to December 2018, in 404 patients with cardiovascular disease, including 267 patients with moderate-to-severe DAS and 137 patients with CRF, mean values of resistive index (RI) and pulsatile index (PI) were obtained from carotid and vertebral arteries. Patients were followed-up for 2.5 years, for primary outcome of HF and MACCE episodes. RESULTS: RI and PI values in patients with DAS compared to CRF were significantly higher, with optimal cut-offs discriminating arterial resistance of ≥0.7 for RI (sensitivity: 80.5%, specificity: 78.8%) and ≥1.3 for PI (sensitivity: 81.3%, specificity: 79.6%). Age, female gender, diabetes, and DAS were all independently associated with increased resistance. During the follow-up period, 68 (16.8%) episodes of HF-MACCE occurred. High RI (odds ratio 1.25, 95% CI 1.13-1.37) and PI (odds ratio 1.21, 95% CI 1.10-1.34) were associated with risk of HF-MACCE. CONCLUSIONS: An accurate assessment of vascular resistance may be used for HF-MACCE risk stratification in patients with DAS.

Etiology and distribution of isolated aortic stenosis in Indian patients - A study from a large tertiary care hospital in north India.

BACKGROUND: Isolated aortic valve disease (IAVD) has traditionally been a disease of elderly, etiology being either senile degeneration of a tricuspid aortic valve or calcification of a bicuspid aortic valve. However, there is scarcity of Indian data regarding demographic distribution and etiological patterns of IAVD in context of emerging therapies like transcatheter aortic valve implantation (TAVR). METHODS & RESULTS: A retrospective observational analysis of 60,560 echocardiograms over three years revealed 3728 newly diagnosed cases of valvular heart disease (VHD). Isolated mitral valve disease (IMVD) constituted 48.7% (n = 1815) of all VHD, including 1104 (29.6%) cases of pure mitral stenosis (MS) which was the commonest single lesion followed by combined mitral and aortic valve disease (CMAVD) (n = 1320, 34.5%), mixed aortic valve disease (MAVD) (n = 349, 9.4%), isolated aortic stenosis (IAS) (n = 179, 4.8%) and isolated aortic regurgitation (IAR) (n = 75, 2.0%). IAS patients had bimodal age distribution with peaks in first and sixth decade, contributed by congenital and acquired IAS respectively. Acquired IAS comprised of degenerative tricuspid aortic valve (n = 79, 58.1%; mean age: 63.2 ± 8.8 years), bicuspid aortic valve (BAV) (n = 34, 25.0%; mean age: 36.0 ± 8.3 years), rheumatic (n = 4, 2.9%; mean age: 55.3 ± 3.4 years) and non-rheumatic IAS with unclear morphology (n = 19, 14%; mean age: 48.5 ± 9.3 years). 65.6% patients with acquired non-rheumatic isolated aortic stenosis were less than 60 years of age. CONCLUSION: In Indian population, senile valvular degeneration is the commonest cause of acquired IAS with majority of them presenting before 60 years of age, thereby bereaving them with the option of TAVR as a treatment modality.

Aortic stenosis: insights on pathogenesis and clinical implications.

Aortic stenosis (AS) is a common valvular heart disease in the Western populations, with an estimated overall prevalence of 3% in adults over 75 years. To understand its patho-biological processes represents a priority. In elderly patients, AS usually involves trileaflet valves and is referred to as degenerative calcific processes. Scientific evidence suggests the involvement of an active "atherosclerosis-like" pathogenesis in the initiation phase of degenerative AS. To the contrary, the progression could be driven by different forces (such as mechanical stress, genetic factors and interaction between inflammation and calcification). The improved understanding presents potentially new therapeutic targets for preventing and inhibiting the development and progression of the disease. Furthermore, in clinical practice the management of AS patients implies the evaluation of generalized atherosclerotic manifestations (i.e., in the coronary and carotid arteries) even for prognostic reasons. In counselling elderly patients, the risk stratification should address individual frailty beyond the generic risk scores. In these regard, the co-morbidities, and in particular those linked to the global atherosclerotic burden, should be carefully investigated in order to define the risk/benefit ratio for invasive treatment strategies. We present a detailed overview of insights in pathogenesis of AS with possible practical implications.

Risk factor profile of calcific aortic stenosis.

BACKGROUND: Calcific aortic stenosis and coronary artery disease share common risk factors. In some of the previous studies statins have been used to retard the progression of aortic stenosis, but the results were inconsistent. METHODS: One hundred and ten patients of CAS above the age of 40 years have undergone clinical, biochemical and echocardiographic evaluation. Coronary angiograms were done in 66% of them. RESULTS: Male to female ratio was 2:1. Patients of CAS with CAD showed higher prevalence of diabetes, hypertension, dyslipidemia, smoking and family history of CAD. Prevalence of obesity and bicuspid aortic valve by echocardiogram was high in those without CAD. CONCLUSIONS: On comparison of prevalence of risk factor in those with and without associated CAD, there was higher prevalence of diabetes (65% vs 30%), hypertension (52% vs 43%), dyslipidemia (69% vs 52%), smoking (24% vs 18%) and family history of CAD (34% vs 16%) in those with associated CAD. The incidence of obesity was higher in those without CAD (20% vs 30%). The difference observed in diabetes alone was found to be statistically significant.

Calcific aortic valve disease: is it another face of atherosclerosis?

Calcific aortic valve disease (CAVD) is the most common valvular heart disease in the elderly. As life expectancy increases, prevalence of CAVD is expected to rise. CAVD is characterized by progressive dystrophic calcification of aortic cusps. In the initial stages, the pathogenesis is similar to atherosclerosis, characterized by basement membrane disruption, inflammation, cell infiltration, lipid deposition, and calcification. Presence of osteopontin in calcified aortic valves suggests pathological calcification and bone formation in these calcified valves. Historical, experimental, genetic, and clinical evidences suggest that CAVD and atherosclerosis share the same pathological sequences with common risk factors. Understanding the two faces of atherosclerosis, the vascular and valvular, will help us to prevent progression of aortic sclerosis to aortic stenosis, by controlling modifiable risk factors and by initiating statin therapy in them. However, the knowledge about these preventive measures and drugs is scanty. In this review article, an attempt is made to unfurl the relation between atherosclerosis and CAVD.